Abstract Improper placement of peripherally inserted central catheters (PICCs) can be life-threatening to pediatric and neonatal patients. PICCs are widely used in pediatrics to provide life-sustaining intravenous therapies, where navigation through the venous system is typically performed blind, or without image-guidance. As a result, up to 48% of pediatric placed PICCs are improperly positioned into the right atrium and require repositioning; the placement of a catheter tip into the heart is associated with a multitude of life-threatening complications such as atrial arrhythmia, heart valve damage, catheter-related right atrial thrombi, and myocardial perforation leading to pericardial effusion. The prevalence of pericardial effusion and consequent cardiac tamponade in neonates with a PICC line placement is 1-3% with 30-50% mortality. Additionally, 13% of PICCs placed into the pediatric population are improperly navigated through the venous system, requiring removal and reinsertion. These complications carry physical and emotional burdens to children and their families. Despite serious adverse events associated with blind placement of PICC lines, guidance systems are not available for neonatal and pediatric patients. The Teleflex ARROW G4 VPS and the Bard Sherlock 3CG are effective for navigation and placement of a catheter tip into the SVC or CAJ in 99% of patients; however, they require the use of catheters that are too large for children. To address the need for accurate and safe vascular access in young patients, TheraNova has developed PICCOLO, an easily operated, point-of-care thermodilution catheter system scaled for real-time vascular access guidance in children. We have designed PICCOLO with the following key innovations: 1) Proprietary thermodilution catheter system provides real-time hemodynamic data for identification of key vascular landmarks, 2) Scalable for use in neonatal and pediatric patients, and 3) Cost-effective and easy- to-use for widespread clinical adoption. Previously, we found that the unique thermodilution signatures of five anatomical locations could be successfully distinguished in vivo with our PICCOLO prototype. Further, we have developed a refined prototype, scaled to the dimensions required for use in neonates, that can identify the SVC from vascular regions that are considered improper and dangerous for placement of PICC tips. The goals of this Phase I proposal are to optimize the system and determine the thermodilution signatures of distinct vascular regions in a weanling pig model. First, we will optimize the signal resolution of the PICCOLO prototype by evaluating saline infusion parameters over varying pulsatile venous flow conditions in a benchtop cardiovascular model (Specific Aim 1). Second, we will compare the thermodilution profiles for PICC tip placement in several key vascular locations as compared to the CAJ in five weanling pigs (Specific Aim 2). The proof-of-concept data obtained through this proposal will demonstrate the use of thermodilution to provide accurate vascular access. These data will also be used to support a Phase II submission, which will include preclinical and clinical studies to validate placement accuracy in neonatal and pediatric patients.